Scn1a gene reactivation after symptom onset rescues pathological phenotypes in a mouse model of Dravet syndrome.
Scn1a gene reactivation after symptom onset rescues pathological phenotypes in a mouse model of Dravet syndrome.
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DOI：
10.1038/s41467-021-27837-w
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发表时间：
2022-01-10
影响因子：
16.6
通讯作者：
Colasante G
中科院分区：
文献类型：
--
作者：
Valassina N;Brusco S;Salamone A;Serra L;Luoni M;Giannelli S;Bido S;Massimino L;Ungaro F;Mazzara PG;D'Adamo P;Lignani G;Broccoli V;Colasante G
Dravet综合征是一种严重的癫痫性脑病，主要由SCN 1A基因的单倍不足引起。反复发作可导致无法治愈的神经功能缺损。这种严重的病理学在症状发作后是否可逆仍不清楚。为了解决这个问题，我们生成了Scn 1a条件性敲入小鼠模型（Scn 1a Stop/+），其中Scn 1a表达可以在小鼠寿命期间按需重新激活。Scn 1a基因破坏导致癫痫发作的发生，通常与癫痫猝死（SUDEP）和行为改变有关，包括从第二/第三周开始的多动，社交障碍和认知障碍。然而，我们发现，Scn 1a基因重新激活时，症状已经表现出来（P30）导致自发性和热诱导癫痫发作的完全救援，行为异常的显着改善和海马快速尖峰interneuron放电的正常化。我们还确定了显着的基因表达变化，包括与Dravet综合征小鼠中的星形胶质细胞增生相关的基因表达变化，因此，在P30时Scn 1a基因表达正常化可以挽救这些变化。有趣的是，Nav1.1生理水平的恢复也挽救了成年Dravet综合征小鼠（P90）在重复发作数月后的癫痫发作。总的来说，这些发现代表了一个坚实的概念验证，强调当Scn 1a基因活性在脑细胞中有效重建时，可以实现疾病表型可逆性。Dravet综合征是由Scn 1a基因单倍型不足引起的一种严重的癫痫性脑病。利用一种新的基因敲入小鼠模型，在这里，作者表明，症状发作后恢复Scn 1a表达足以挽救该综合征的主要表型表现。
Dravet syndrome is a severe epileptic encephalopathy caused primarily by haploinsufficiency of the SCN1A gene. Repetitive seizures can lead to endurable and untreatable neurological deficits. Whether this severe pathology is reversible after symptom onset remains unknown. To address this question, we generated a Scn1a conditional knock-in mouse model (Scn1a Stop/+) in which Scn1a expression can be re-activated on-demand during the mouse lifetime. Scn1a gene disruption leads to the development of seizures, often associated with sudden unexpected death in epilepsy (SUDEP) and behavioral alterations including hyperactivity, social interaction deficits and cognitive impairment starting from the second/third week of age. However, we showed that Scn1a gene re-activation when symptoms were already manifested (P30) led to a complete rescue of both spontaneous and thermic inducible seizures, marked amelioration of behavioral abnormalities and normalization of hippocampal fast-spiking interneuron firing. We also identified dramatic gene expression alterations, including those associated with astrogliosis in Dravet syndrome mice, that, accordingly, were rescued by Scn1a gene expression normalization at P30. Interestingly, regaining of Nav1.1 physiological level rescued seizures also in adult Dravet syndrome mice (P90) after months of repetitive attacks. Overall, these findings represent a solid proof-of-concept highlighting that disease phenotype reversibility can be achieved when Scn1a gene activity is efficiently reconstituted in brain cells. Dravet syndrome is a devastating epileptic encephalopathy caused by Scn1a gene haploinsufficiency. Exploiting a novel knock-in mouse model, here the authors show that restoring Scn1a expression after symptom onset is sufficient to rescue main phenotypic manifestations of the syndrome.
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DOI：
10.1007/978-1-4939-3572-7_13
发表时间：
2016-01-01
期刊：
DATA MINING TECHNIQUES FOR THE LIFE SCIENCES
影响因子：
--
作者：
Dobin, Alexander;Gingeras, Thomas R.
通讯作者：
Gingeras, Thomas R.
影响因子：
6.1
作者：
Arion, D;Sabatini, M;DeFelipe, J
通讯作者：
DeFelipe, J
影响因子：
25
作者：
Chan KY;Jang MJ;Yoo BB;Greenbaum A;Ravi N;Wu WL;Sánchez-Guardado L;Lois C;Mazmanian SK;Deverman BE;Gradinaru V
通讯作者：
Gradinaru V
影响因子：
4.5
作者：
Hawkins, Nicole A.;Zachwieja, Nicole J.;Kearney, Jennifer A.
通讯作者：
Kearney, Jennifer A.
影响因子：
11.1
作者：
Hsiao J;Yuan TY;Tsai MS;Lu CY;Lin YC;Lee ML;Lin SW;Chang FC;Liu Pimentel H;Olive C;Coito C;Shen G;Young M;Thorne T;Lawrence M;Magistri M;Faghihi MA;Khorkova O;Wahlestedt C
通讯作者：
Wahlestedt C